Hannelore Zierler

Familial Mental Retardation Syndrome ATR-16 Due to an Inherited Cryptic Subtelomeric Translocation, t(3;16)(q29;p13.3)

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Novel and Recurrent Mutations in Patients with Androgen Insensitivity Syndromes

Background/Aims: Androgen insensitivity syndrome (AIS) caused by mutations within the androgen receptor gene represents a variety of phenotypes from females with 46,XY karyotype over individuals with ambiguous genitalia to infertile males. Methods: We studied 24 patients with AIS by sequencing androgen receptor gene. 19 of the investigated patients were affected by complete androgen insensitivity syndrome (CAIS) and 5 suffered from partial androgen insensitivity syndrome (PAIS). Results: So far we have detected 12 unreported mutations as well as 9 recurrent mutations (3 recurrent mutations were detected twice) in exons 2–8 of the androgen receptor gene. Three of the novel mutations cause a frameshift with subsequent premature termination and were found in patients with CAIS. These frameshifts were induced by single nucleotide deletion or insertion, or in one case by a 13-bp deletion, respectively. Another premature stop codon found in a CAIS patient results from an already reported nucleotide substitution in exon 5. Furthermore, in a CAIS patient we found a novel duplication of codon 788. All other mutations caused single base substitutions spread through exons 2–8 and were associated with CAIS or PAIS. Conclusions: We report a broad spectrum of different mutations within the AR gene leading to various manifestations of AIS. Apart from truncating mutations, a reliable genotype/phenotype correlation cannot be established. Therefore, modifying factors must be effective.